AZD0156

The imidazo[4,5-c]quinolin-2-one derivative, AZD-0156, is an exceptionally potent ATM inhibitor, with both picomolar activity in vitro (IC50 = 0.04 nM) and in cells (IC50 = 0.57 nM). AZD-0156 was profiled against a large panel of 397 kinases at 1 µM and showed a high degree of selectivity over closely related kinases up to 1 µM. Cellular activity for other PIKK kinases such as ATR, MTOR, and PI3K was >1000-fold therefore serving as a high-quality probe targeting ATM. Moreover, AZD0156 has high levels of solubility in biorelevant media such as phosphate buffer at pH 6.5. AZD0156 showed good exposure in mice following oral administration and completed phase I clinical trials. The compound is well tolerated in mice even at 20 mg/kg. However, it should be noted, that no significant efficacy was observed when AZD0156 was administered as monotherapy.

This compound is a potent in vitro and in vivo tool compound for assessing ATM with high kinase selectivity. While prior analogs were beneficial for in vitro profiling, this compound is suitable for in vivo work. While the overall PK parameters in mouse are not disclosed, the authors note good efficacy in combination with other agents up to 20 mpk QD on intermittent dosing.